Question 9

Outline the classification, structure and distribution of the opioid receptors (50% marks). Describe the intracellular events following opioid receptor activation (50% marks).

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College Answer

This question was asked in a specific way to provide candidates with a template for their answer. The
classification most commonly used for opioid receptors (μ(MOP), δ(DOP), k(KOP) & NOP) and a
description of the important characteristics or differences between them was expected. A description oftheir central and peripheral distribution was required including specific central nervous system sites such as pre and post synaptic locations in the brain (ie. the periaqueductal gray, locus ceruleus and
amygdala) and spinal cord (ie. primary afferent neurons in the dorsal horn).
Opioid receptors as a class are transmembrane spanning G protein receptors that have significant
downstream effects including presynaptic inhibition of neurotransmitters of primary afferent neurons
such as noradrenaline and substance P, and postsynaptic inhibition of membrane depolarization of
dorsal horn nociceptive neurons. Specifity of detail in descriptions of these actions was expected. 

Discussion

Classification of opioid receptors:

  • There are four main types: μ, κ, δ and the NOP receptors (nociceptin-orphanin)
  • μ-opioid receptors are responsible for much of the analgesia, but also for the respiratory depression, constipation and cardiovascular effects
  • δ-opioid receptors seem to be involved in respiratory depression, constipation and mood
  • κ-opioid receptors are implicated in the sedation and confusion seen with opioid use
  • NOP receptors seem to have an anti-analgesic, pronociceptive effect, and NOP receptor antagonists have analgesic effects

Structure  of opioid receptors:

  • Opioid receptors are transmembrane-spanning G-protein-coupled receptors
  • Their natural ligands are endorphins and encephalins 
  • The G-proteins are inhibitory Gi or Go proteins

Distribution of opioid receptors:

  • The receptors are distributed unevenly though the CNS.
  •  μ-opioid receptor are mostly found in
    • dorsal horn of the spinal cord: μ-receptors are present presynaptically on primary afferent neurons (where they have an inhibitory influence on neurotransmission)
    • Periaqueductal grey matter: This part of the brainstem sends descending efferents which act to inhibit nociceptive transmission in afferent fibres; μ-receptors remove some of the GABA-ergic inhibitory tone which regulates this descending inhibition

Intracellular events following opioid receptor activation:

  • The receptors are directly coupled to potassium and voltage-sensitive calcium channels
  • By activating, they increase potassium conductance and decrease calcium conductance
  • Increased potassium conductance leads to membrane hyperpolarisation
  • Closure of calcium channels decreases the availability of intracellular calcium which is essential for neurotransmitter release
  • Ergo, the net effect of binding presynaptic opioid receptors is to decrease synaptic neurotransmission by preventing neurotransmitter release
  • Also, these receptors inhibit adenylate cyclase, which reduces the formation of cAMP, and results in the hyperpolarisation of neurons
  • Activation of the receptors is therefore inhibitory for neurotransmission

References

Zöllner, C., and C. Stein. "Opioids." Handbook of Experimental Pharmacology (2006): 31-63.

Crow, Jessica R., Stephanie L. Davis, and Andrew S. Jarrell. "Pharmacology and Pharmacokinetics of Opioids in the ICU." Opioid Use in Critical Care. Springer, Cham, 2021. 31-64.

Cata, Juan P., and Shreyas P. Bhavsar. "Pharmacology of opioids." Basic Sciences in Anesthesia. Springer, Cham, 2018. 123-137.

Chahl, Loris A. "Opioids-mechanisms of action." (1996).

Waldhoer, Maria, Selena E. Bartlett, and Jennifer L. Whistler. "Opioid receptors." Annual review of biochemistry 73.1 (2004): 953-990.

Pasternak, Gavril W. "Molecular biology of opioid analgesia." Journal of pain and symptom management 29.5 (2005): 2-9.